Glycolysis supports EGFR-mutant Lung Adenocarcinoma Cell Survival by blocking Autophagy-mediated EGFR Degradation
Session type: Poster / e-Poster / Silent Theatre session
Oncogenic epidermal growth factor receptor (EGFR) is essential for the development and growth of non-small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear.
We studied the effect of EGFR on metabolism via targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomic analysis, glucose consumption and lactate production assay, and extracellular acidification and oxygen consumption assay in NSCLCs. Mechanisms regulating EGFR stability were investigated using RNA interference/pharmacological inhibitors followed by immunoblotting, cell death assay, and functional assays. Therapeutic potential of JNK activator was determined by monitoring cell growth and death and in mouse xenograft models. Immunohistochemistry was used to analyze JNK phosphorylayion and EGFR expression in NSCLC tissues (n=244). All statistical tests were two-sided.
EGFR knockdown in EGFR-mutant NSCLC significantly decreased the levels of glycolytic pathway intermediates (p < 0.05) via transcriptional regulation of glycolytic genes. EGFR-mutant NSCLCs exhibited significantly elevated glucose uptake and lactate production compared with EGFR-WT NSCLCs. Glucose deprivation markedly triggered EGFR-mutant NSCLC cell death through robust reduction of EGFR levels, but had no significant effects on EGFR-WT NSCLCs. EGFR-mediated enhanced glycolysis was a major source of carbon for TCA cycle in EGFR-mutant NSCLC, which is essential for maintaining EGFR levels. Glucose deprivation-mediated mitochondrial ATP depletion enhanced reactive oxygen species accumulation and subsequent JNK-mediated autophagy activation, which in turn induced EGFR degradation. The expression of phosphorylated JNK was significantly decreased in patients with EGFR-mutant NSCLCs (7.94%) compared with WT EGFR (23.28%) (p =0.001). A reverse correlation between phosphorylated JNK and EGFR expression was observed in all tissues regardless of EGFR mutation (p =0.0394).
These data suggest that enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels through inhibition of JNK-induced autophagy, providing a promising rational for exploring JNK activators for patient bearing EGFR-mutation NSCLC.